UPMC surgeons perform second baboon to
human liver transplant

PITTSBURGH, Jan. 11, 1993--Surgeons from the University of Pittsburgh Medical
Center (UPMC) announced they performed the world's second baboon-to-human liver transplant
on a 62-year-old man dying from hepatitis B, for whom there was not the option of a
human-to-human transplant. The 13-hour operation began Jan. 10, 1993 at 11:15 a.m. and
ended at 12:35 a.m. Jan. 11. Some modifications in the procedure and treatment were made
by the transplant team based on recent research advances and knowledge gained from its
first attempt on a 35-year-old man who was transplanted on June 28, 1992.

According to a report published in the British medical journal, The Lancet, the
first patient died of a brain hemorrhage caused by a fungus infection 71 days after his
transplant. Obstruction in the liver's bile ducts by sludge, a semi-solid substance
comprised of cholesterol and bile pigments, and complications of immunosuppression with an
otherwise effective combination of drugs may have also contributed to his death, the Pitt
team reported.

Based on these results, surgeons are changing the timing of doses of the
immunosuppressant drugs used, in particular, cyclophosphamide, so that the risk of
infection is reduced. The combination of drugs remains the same: FK506, cyclophosphamide,
prostaglandin, and prednisone.

To better detect sludge formation, surgeons John Fung, M.D., Ph.D.; Satoru Todo, M.D.;
and Andreas Tzakis, M.D., inserted a tube into the baboon liver's primary duct and guided
it outside the patient's abdomen during the operation. The tube allows the ducts to be
flushed in order to prevent or clear any formation of sludge and also permits more
conclusive diagnostic studies to be performed during the patient's recovery.

As a measure to promote acceptance of the transplanted liver, surgeons infused a
suspension of white blood cells from the baboon's bone marrow into a vein of the
recipient. The procedure took place as follows: while the transplant surgery was underway,
a separate team of surgeons was isolating and purifying the cells from the donor's bone
marrow. Ten hours later, as the new liver was being sewn in, the cell transplant team
began infusing a small quantity of the cell suspension into a vein in the recipient's
neck. The infusion of cells began at 9:20 p.m. and took approximately one hour.

"While the combination of four drugs we used in the first case was shown to be
effective in controlling rejection, we believe the bone marrow infusion in the second
patient will be an extra boost to produce chimerism and enhance acceptance of the new
organ," said Thomas E. Starzl, M.D., Ph.D., director of Pitt's Transplantation
Institute. "The transfusion contains the immune system cells we believe are important
for chimerism," he added.

Chimerism is the cellular environment consisting of both recipient and donor cells,
which the Pitt team believes is necessary for acceptance of transplanted organs. It has
recently been identified in successful animal and human transplant recipients by the Pitt
researchers and was also evident in the first baboon liver recipient. Baboon cells were
found in the patient's blood during his life, and at autopsy, cells were found in his
heart, lungs, kidneys, and lymph nodes.

"The introduction of the donor's immune system cells to the recipient's own immune
system promotes a state of acceptance. Immune system cells from the donor should protect
the transplanted liver by preventing the recipient's immune system cells from launching an
attack. In addition to their immunosuppressant properties, we believe the drugs also act
as facilitators of communication between the donor and recipient immune system
cells," explained Dr. Fung, chief of transplantation and an associate professor of
surgery.

Injecting bone marrow cells promotes a cellular environment that reduces the chances of
rejection even more than is possible with drugs alone.

According to the surgeons' Lancet report, the four drugs, in the absence of bone marrow
cells, effectively prevented antibody-mediated rejection, the primary obstacle to
successful cross-species transplantation. Antibody-mediated, or humoral, rejection occurs
when the immune system's B cells cause the production of antibodies that attack the donor
organ. Augmented with standard steroid treatment, the drugs also controlled a minor
episode of cellular rejection that occurred early in the first patient's clinical course.
Rejection of this kind involves T cells.

FK506, a drug manufactured by Fujisawa Pharmaceutical Co., Ltd., of Japan and developed
at Pitt to combat rejection, works to suppress the recipient's T cells from attacking the
donor organ. Cyclophosphamide, a Bristol-Myers Squibb drug developed to treat cancer, was
shown to hold promise for transplant recipients by Dr. Starzl more that 20 years ago.
Commercially known as Cytoxan, cyclophosphamide prevents B cells from proliferating, a
process which occurs in the presence of an antigen -- a foreign substance -- and results
in the production of antibodies that help destroy the foreign substance. It is
cyclophosphamide that the Pitt team is modifying the way it is administered in the second
baboon liver recipient.

The two other drugs that make up the four-drug cocktail are prednisone, a steroid
hormone that affects those cells which help to recognize and process antigens, and
prostaglandin, which serves to subdue the chain reaction of events likely to occur in the
immune system response.

Pitt's Institutional Review Board gave its approval to the transplant team to proceed
with four baboon-to-human liver transplants, contingent on case-by-case review, for
patients with chronic, active hepatitis B. Hepatitis B is considered by many members of
the transplant community to be a contraindication for human-to-human liver transplantation
because of the great likelihood the disease will recur in the newly transplanted
liver.

"Baboons do not appear to be able to be infected with hepatitis B, so as sources
for organs, they may offer a solution for these patients," said Dr. Starzl before the
first transplant.

Surgeons were encouraged that there was no evidence of the viral infection in the first
recipient's liver when examined at autopsy, but said he did not live long enough to state
conclusively that a baboon's liver, when transplanted, is indeed resistant to hepatitis B.

The baboon was also selected as a source because it is not an endangered species and
can be bred safely and easily in captivity.

Cross-species transplantation, or xenotransplantation, has long been considered an
answer to the critical shortage of available human donor organs. While patient waiting
lists have become longer, the inadequate supply of donor organs persists. Nationwide, at
least one patient dies each day while waiting for a liver transplant, and this figure has
increased each year.

Although early attempts at xenotransplantation date back as far as 1905, new
understanding of the immune system and subsequent new drugs created the scientific climate
for several attempts in the 1960s, at a time when dialysis treatment and cadaver organs
were not widely available. In 1963 and 1964, Keith Reemtsma, M.D., performed
chimpanzee-to-human kidney transplants in 12 adults at Tulane University. One recipient
lived with the kidney for nine months without evidence of rejection before dying of an
infection. Soon after this series, other surgeons made unsuccessful attempts to transplant
a chimpanzee heart and kidney, and Dr. Starzl performed kidney transplants in six adults
using baboon donors. Between 1969 and 1974, Dr. Starzl provided chimpanzee livers to three
children, one of whom lived 14 days before succumbing to sepsis, a widespread infection.
Surgeons at Loma Linda University had available the anti-rejection drug cyclosporine when
Baby Fae received a baboon heart in 1984. The infant died of rejection 20 days after
surgery. Between 1963 and 1984, 28 clinical procedures involving solid organs from animal
donors were performed in the United States and South Africa.

In addition to the world's first baboon liver transplant last year, a
woman at the Cedars-Sinai Medical Center in Los Angeles lived with both her own liver and
a pig's liver for 32 hours while awaiting a suitable human donor.